Prostaglandin-dependent modulation of dopaminergic neurotransmission elicits inflammation-induced aversion in mice
Michael Fritz, … , Anders Blomqvist, David Engblom
Michael Fritz, … , Anders Blomqvist, David Engblom
Published December 21, 2015
Citation Information: J Clin Invest. 2016;126(2):695-705. https://doi.org/10.1172/JCI83844.
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Research Article Neuroscience

Prostaglandin-dependent modulation of dopaminergic neurotransmission elicits inflammation-induced aversion in mice

Abstract

Systemic inflammation causes malaise and general feelings of discomfort. This fundamental aspect of the sickness response reduces the quality of life for people suffering from chronic inflammatory diseases and is a nuisance during mild infections like common colds or the flu. To investigate how inflammation is perceived as unpleasant and causes negative affect, we used a behavioral test in which mice avoid an environment that they have learned to associate with inflammation-induced discomfort. Using a combination of cell-type–specific gene deletions, pharmacology, and chemogenetics, we found that systemic inflammation triggered aversion through MyD88-dependent activation of the brain endothelium followed by COX1-mediated cerebral prostaglandin E2 (PGE2) synthesis. Further, we showed that inflammation-induced PGE2 targeted EP1 receptors on striatal dopamine D1 receptor–expressing neurons and that this signaling sequence induced aversion through GABA-mediated inhibition of dopaminergic cells. Finally, we demonstrated that inflammation-induced aversion was not an indirect consequence of fever or anorexia but that it constituted an independent inflammatory symptom triggered by a unique molecular mechanism. Collectively, these findings demonstrate that PGE2-mediated modulation of the dopaminergic motivational circuitry is a key mechanism underlying the negative affect induced by inflammation.

Authors

Michael Fritz, Anna M. Klawonn, Anna Nilsson, Anand Kumar Singh, Joanna Zajdel, Daniel Björk Wilhelms, Michael Lazarus, Andreas Löfberg, Maarit Jaarola, Unn Örtegren Kugelberg, Timothy R. Billiar, David J. Hackam, Chhinder P. Sodhi, Matthew D. Breyer, Johan Jakobsson, Markus Schwaninger, Günther Schütz, Jan Rodriguez Parkitna, Clifford B. Saper, Anders Blomqvist, David Engblom

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Figure 4

Inflammation-induced aversion is dependent on striatal EP1Rs.

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Inflammation-induced aversion is dependent on striatal EP1Rs. (A) Microg...
(A) Micrograph demonstrating D1R-specific recombination in preproenkephalin-negative (ppEnk-negative) neurons in the striatum. ppEnk is used as a marker of D2R-positive neurons. (B) Inflammatory aversion is blocked in mice lacking EP1Rs (n = 10) compared with controls (n = 5) but rescued to a normal level when EP1Rs are reexpressed in D1R-expressing neurons (n = 7). (C) Conditioning with microinjections of NaCl in either caudate putamen (CPu) or nucleus accumbens (NAc) (n = 7) or PGE2 in the NAc (n = 4) or CPu (n = 4). PGE2 injected into the dorsal striatum induced aversion, whereas the other injections did not. (D) Plot of approximate microinjection sites for the injections made with PGE2 in C. (E and F) PGE2 levels in the dorsal striatum (n = 7, NaCl; 8, LPS) and the nucleus accumbens (n = 7, NaCl; 10, LPS) after injections of NaCl or LPS i.p. (G) PGE2 levels in the CPu after a single LPS injection in mice lacking COX-1 (n = 4, NaCl; 8, LPS). (H) Representative injection site of viral vectors expressing Cre recombinase in the striatum (CPu), not affecting the cerebral cortex (Ctx). A Cre-dependent reporter virus, expressing EGFP upon recombination, was coinjected with the Cre virus. (I) Aversion scores in control mice and mice with a rescue of EP1Rs in the striatum (n = 5 and 5, respectively). Both groups were injected with Cre-expressing viral vectors. Scale bars: 25 μm (A) and 200 μm (H). *P < 0.05, **P < 0.01, ANOVA followed by Bonferroni’s (B) or Dunnet’s (C) post hoc test, or Student’s t test (E–G and I).